Strategies towards the Synthesis of Azetidine-Containing Metabolites Produced by Pseudomonas aeruginosa

项目摘要/摘要 含氮替丁代谢物的全合成(氮杂甲酰胺A、氮杂多糖酮和氮杂环己酮) 从铜绿假单胞菌中分离出来的重氮硫酸酯)并不存在，而且急需，所以他们的生物 可以评估仲裁感应行为中的函数。特别是，它们的确切生产模式 非核糖体多肽合成酶(NRPS)的酶簇尚不清楚；此外，还阐明了 这些代谢物在调节铜绿假单胞菌群体感应行为中的作用目前还不可能 到自然细菌系统中产生的微量代谢物。此外，这些代谢物 影响整个细菌生物被膜的形成和氧化还原活性代谢物的产生，这部分是 与感染铜绿假单胞菌的囊性纤维化患者的不良结局有关。因此，总的合成 这些代谢物是非常需要的，并将通过扩大我们的 了解铜绿假单胞菌生物膜的形成，并潜在地开发抗毒力 对它的长期治疗。 本建议中描述的研究试图开发合成这些新型氮杂环丁胺的策略-- 含有代谢物的。重要的是，我们提出了减少总体目标风险的正交方法 同时仍然通过在复杂的环境中利用现代化学来推动化学边界。用于合成 Aim1)，我们的设计涉及到访问和使用独特的ynamide级联来 环化系统；第二种方法利用酶生物催化来安装酒精立体中心。 对于二氮替多莫比里酮的合成(目标2)，我们首先提出了获得 氮杂多吡酮前体。最初的方法将建立在现有化学的基础上，利用钯催化的 在复杂的环境中与CO的级联环化反应；另一种方法减轻了前者的风险 通过利用缩合反应性来安装必要的循环系统。要访问 从氮杂多普利酮出发，我们设想了两种方法。第一种是使用仿生体 对文献先例的反思--直接将氮杂多吡酮与氮替多莫尼胺A反应 在碱性条件下自发反应，获得目标代谢物。此外，我们建议访问 通过一种生物启发的方法，利用环的形成来控制烯烃的几何构型。 总体而言，这项拟议的研究具有重要意义，因为它为建立第一个 氮甲草酰胺A、氮杂多糖酮的全合成，为其生物学研究奠定了基础。更广泛地说， 这些策略可以用来在其他细菌代谢产物中获得类似的支架 合成的。在加州理工大学雷斯曼教授的团队中进行这项研究，与他们目前的成功很好地吻合 在复杂的天然产物的高效全合成方面，并将加强我先前在有机金属方面的培训 化学为我未来的学术生涯做好准备，成为一名教授。

Project Summary/Abstract Total syntheses of novel azetidine-containing metabolites (azetidomonamide A, azetidopyridone, and diazetidomonapyridone) from Pseudomonas aeruginosa do not exist, and are sorely needed so their biological functions in quorum-sensing behavior can be evaluated. In particular, the exact mode of their production from the non-ribosomal peptide synthetase (NRPS) enzymatic cluster is unknown; furthermore, elucidating the exact role of these metabolites in modulating quorum-sensing behavior in P. aeruginosa is not currently possible due to the minute quantities of metabolites produced in the natural bacterial system. Additionally, these metabolites affect overall bacterial biofilm formation and the production of redox-active metabolites, which are partially implicated in adverse outcomes for cystic fibrosis patients infected with P. aeruginosa. Thus, total syntheses of these metabolites are highly needed and will have a broader impact on human health through expanding our understanding of biofilm formation by P. aeruginosa, and potentially allowing for development of anti-virulence treatments for it in the long term. The studies described in this proposal seek to develop strategies for synthesis of these novel azetidine- containing metabolites. Importantly, we propose orthogonal approaches that mitigate the risk of the overall goal while still pushing chemical boundaries by leveraging modern chemistry in complex contexts. For the synthesis of azetidomonamide A (Aim1), our design involves accessing and employing a unique ynamide cascade to cyclize the system; a second approach utilizes enzymatic biocatalysis to install the alcohol stereocenter. For the synthesis of diazetidomonapyridone (Aim 2), we first propose strategies for accessing the azetidopyridone precursor. The initial approach would build on existing chemistry by utilizing a Pd-catalyzed cascade cyclization with CO in a complex setting; an alternative approach alleviates the risk of the former approach by employing condensation reactivity to install the requisite cyclic system. To access diazetidomonapyridone from the azetidopyridone, we envision two approaches. The first employs a biomimetic reflection of literature precedent by directly subjecting azetidopyridone to azetidomonamide A, which undergo spontaneous reaction under basic conditions to access the target metabolite. Additionally, we propose accessing diazetidomonapyridone via a bio-inspired approach that leverages ring formation to control alkene geometry. Overall, the proposed research is significant because it provides creative strategies to establish the first total syntheses of azetidomonamide A, azetidopyridone, which will enable their biological study. More broadly, these strategies can be used to access similar scaffolds in other bacterial metabolites that have yet to be synthesized. Performing this research in Prof. Reisman’s group at Caltech aligns well with their current success in the efficient total synthesis of complex natural products and will augment my prior training in organometallic chemistry to prepare me for a future academic career as a professor.